#384 - Special episode — Obicetrapib: The CETP inhibitor with cardiovascular benefits and potential Alzheimer's prevention

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If you want to learn more about the benefits of our premium membership, head over to peteratiamed.com/subscribe. [MUSIC] Welcome to a special episode of the Drive. In this episode, I take a slightly different approach,

where I'm going to walk you through a single topic in depth, breaking down the science behind. In this case, a drug that caught my attention and has me very excited. The drug is called ObesetraPip. So I'm going to explain what it is, why it's generating renewed interest

in cardiovascular medicine, at least as a class of drug, and why the emerging data may also have implications for Alzheimer's disease, particularly for those who carry an e4 allele. So in this episode, I'm going to discuss what ObesetraPip is, how it works as a class of drug called a CETP inhibitor,

the history of these drugs and why the previous versions of them have failed. In some cases, spectacularly, the key clinical trials behind ObesetraPip, and why they were designed, what they were designed to measure, the drugs affect on the major lipid biomarkers,

including LP L.P. L.A., all very interesting. A study called the Broadway biomarker study, and its findings in Alzheimer's related blood biomarkers, again, including a very interesting subgroup in apoe carriers. And I guess most of all, what these results mean,

“how do they have me thinking about this drug for my patients?”

I hope you enjoy this special episode of The Drive. So if you spend any time thinking about Alzheimer's disease research, you get pretty familiar with the emotional whiplash that accompanies it. One week, you're going to see a biomarker that moves and people talk about it, and you'll see reportings all over the sort of lay press.

And then the next week, some trial misses and the whole idea gets dismissed. And I think that's understandable for reasons, maybe beyond the scope of what I want to talk about today, and I think it's also really true in the cases of prevention, because prevention trials are hard to conduct.

They take a long time, they're very expensive, and early signals can look compelling, even before something's actually proven. So with that as background, today I'd like to talk about a drug called ObacetraPip.

Now this is a drug that's primarily being investigated because of its ability to reduce LDL cholesterol and with a depob. And I'm going to talk about that as part of the story. But more broadly, I want to talk about this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease.

So here's why it's interesting. ObacetraPip is a CETP or C-TEP inhibitor, which is a class of drug with a very complicated and quite honestly a very fascinating history and cardiovascular disease medicine. I'm not actually talking about this in detail,

“because I think it's important to the story.”

But in a recent large phase three lipid trial, there was a pre-specified biomarker study that looked at Alzheimer's related blood biomarkers for a period of about 12 months. And in these studies, or in this study rather, the investigators saw an attenuation of P-Tau 2017 progression

with a very strong signal in the APO E44 individuals.

So this combination, which is basically a revived drug,

a drug that there's lots of examples of this class of drug in the graveyard, plus a coherent biomarker movement, coupled with real genotype specificity, is in my mind what makes this a very exciting topic that I want to share with you all today.

To set expectations, I'm not going to come away from this proving that obacetropid prevents Alzheimer's disease, or delays even cognitive benefits. But I will say that I haven't been as excited about any drug in the market, or a drug that's about to enter the market as I am with respect to this drug. So what do I want to accomplish here today?

First, I want to kind of revisit the story of C-Tep inhibitors. Why so many of them have failed? I want to explain why, maybe this drug is not failing. Explain why lipid biology intersects with Alzheimer's disease,

I want to walk through the very specific study that is leading me to have this optimism.

It's called the Broadway study. And I want to talk about what I hope happens next, so that we can figure out whether this needs to be a part of everybody's life who's at risk. So to start, let's get into C-E-T-P or C-Tep biology. Now, to understand why this class of drug works,

“you have to understand something called reverse cholesterol transport.”

And to understand how reverse cholesterol transport works, you kind of got to go back and understand life of proteins. So apologies in advance for those of you that are already completely up to speed on life of proteins, but I just want to make sure everybody's playing on the same level. Now, the way I talk about this with my patients is the way I'm going to kind of talk about it with you,

which is to say that there are broadly speaking two classes of life of proteins. Let's not forget why we have life of proteins. Life of proteins exist so that we can move cholesterol through our bloodstream. Why is that important? Well, there are several factors.

The first is every cell in the body needs cholesterol.

It's a vital ingredient for our existence. If we didn't make cholesterol, we wouldn't actually be alive, and not every cell can necessarily make enough at every moment in time. So while every cell can make it, cholesterol needs to be shared across the body. Now the problem with cholesterol is it is not water soluble.

So the fancy word for that is it is hydrophobic. And so something that is hydrophobic or something that repels water, can't be transmitted through the blood because the blood is water. Our blood is plasma and a bunch of proteins. So the body has to come up with a slick way to do this.

Again, the body has no trouble transporting things that are water soluble. So proteins, electrolytes, ions. These things move easily through the blood glucose for that matter, just doesn't need anything to carry it. Not the same for cholesterol.

So we evolved these cool things called lipo proteins, which is the name suggests or part lipid, part protein. The lipid or cholesterol fits on the inside. So it's shielded from the hydrophilic exterior. And the proteins are on the outside, which is what allows it to transmit through the blood.

Now you can broadly divide these into two classes. There's an Apo B class and there's an Apo A1 class. The Apo B class is the one you've heard me talk about a ton because those Apo B lipoproteins are the ones that cause atherosclerosis.

Now they're mostly LDLs. But we shouldn't forget how they start. They start out as VLDLs, very low density lipoproteins, which are big, really big. And they show up in all sorts of sizes.

There's like they cascade from a V6 to a V1 in size. They spend a tiny, tiny fraction of time as ideals, intermediate density lipoproteins, before ultimately maturing as LDLs or low density lipoproteins. And so if you did a blood test,

you might look at the cholesterol concentration of these.

You would never be able to catch an ideal,

but you would certainly catch the VLDL cholesterol. And that level might be 15 to 20, maybe as high as 30 milligrams per deciliter. And then you would look at the LDL cholesterol, and you would see a much bigger number.

“Now remember, the LDLs are actually smaller,”

but you have so many more of them than the VLDLs, and therefore you're going to an aggregate find much more cholesterol per unit volume of plasma. Now on the other side of the ledger, we have these things called HDLs or high density lipoproteins,

and they're structurally different. They come from a different lineage, and they have a different lipoprotein that wraps around them. And that lipoprotein is called APO-A1. This is going to be important as we get into our story.

So what is reverse cholesterol transport? Well, historically it has simply been viewed as HDLs returning cholesterol molecules from the body to the liver. And so if you asked me 10 years ago

to tell you what RCT or reverse cholesterol transport was, that's what I would've said. I would've said it's in HDLs. Take the D lipidate, you know, for example, plaques in the coronary arteries,

and they'll, or they take a sort of cholesterol out of other tissues, and they bring it back to the liver.

“But I think we would now want to more technically refer”

to that term as HDL or APO-A1 mediated trafficking of cholesterol. And again, that process is when a peripheral cell exports excess free cholesterol to that protein, the APO-A1 protein that forms the HDL particle. That cholesterol is then packaged into a more stable form,

carried with the HDL particle returns back. Okay, now the direct RCT or reverse cholesterol transport is when the HDL delivers that cholesterol straight into the liver, sometimes the intestine, and it unloads it there via a receptor,

called the sterile receptor binding one or SRB one. I only mention that because I'm going to bring it up later.

But just remember that HDLs can take cholesterol directly

“to the liver and they deliver it through that receptor.”

But there's also something called indirect RCT. I don't think I even learned what indirect RCT was until maybe eight or nine years ago, which is not to say it wasn't understood before then I'm just telling you I didn't understand this before then.

And here is where this is actually kind of cool. The HDL doesn't deliver the cholesterol itself. Instead, it exchanges its cholesterol ester which are the cholesterol molecules bound to long chain fatty acids.

So that's a cholesterol ester and cholesterol, you know, cousins. It exchanges those things for the triglycerides inside the APOB particle, which is usually the LDL. So let's just go back and say that again.

So you got an HDL that's full of cholesterol ester. It bumps into an LDL in the periphery, which has got a bunch of triglycerides in it. They swap triglyceride for cholesterol ester and then those LDL particles,

quote unquote bad guys, do a good thing. They take cholesterol back to the liver. Now, it's important to understand that an enormous amount of reverse cholesterol transport takes place via this route.

So I'm 40 to 50% of it. So, you know, it's important to understand that LDLs aren't all bad. They are doing this one good thing. Now, I know what you're thinking if we lower our LDLs

“does that mean we get less reverse cholesterol transport?”

No, the direct pathway just picks up the balance, but it's just an interesting thing to observe here. Okay, now what does all this thing have to do with C-Tep? Well, what does C-Tep stand for? I said it, I think, at the beginning.

It stands for cholesterol ester transfer protein. And so at a high level, you can think of the C-Tep as a molecular shuttle that exchanges the cholesterol ester in the HDL for the triglyceride molecule in the LDL as part of this indirect reverse cholesterol transport pathway.

Now, because C-Tep mediates an exchange of cholesterol ester from HDL for triglyceride in the APOB containing particles, it doesn't just move cholesterol. It actually reshapes the particles themselves. And so, when C-Tep activity is high,

more cholesterol esters enter, but per me leave the HDL and move into the LDL. So HDL becomes cholesterol poor and triglyceride rich. Well, LDL becomes cholesterol rich and triglyceride poor. Okay, but remember, while we like the idea of cholesterol

going back to the liver, if you just load those LDLs of cholesterol,

we know where they're ultimately going to end up.

So this is not a condition we want. So the problem with too much C-Tep activity is that the triglyceride enriched HDL is unstable. It gets rapidly trimmed down by enzymes called lipases, both in the liver and at the endothelium.

These produce smaller HDL particles that can either be rebuilt or cleared from circulation, but what happens is that you have those cholesterol enriched LDL particles that will ultimately go back to the liver, but may not, right? They may also end up ending up in artery walls.

“So that's what's happening when C-Tep is activated.”

And so what happens if you inhibit C-Tep, the opposite happens? So less cholesterol ester leaves HDL. This results in much larger cholesterol rich HDL particles. So HDL cholesterol, the biomarker goes up, and LDL cholesterol, the biomarker goes down.

Alright, so with that as background, I think we can now talk about what I think is a very fascinating history of this class of drug called C-ETP or C-Tep inhibitors. Now it's important to understand the context of this. So in the 90s, I think around the 90s,

when this class of drug were first developed,

the excitement was almost entirely around the HDL story. What do I mean by that? Well, the C-Tep inhibitors, these first versions, which we'll talk about, dramatically raised HDL cholesterol, oftentimes doubling it, okay? Now at the time, this term that still exists today,

unfortunately, was even more prevalent, which was that HDL was good cholesterol. And so the thinking was really straightforward in its reductionist manner, which was if low HDL is bad, because it's associated with more cardiovascular risk,

then raising HDL should be good. And therefore, giving a drug that raises HDL cholesterol is a good thing, and that was the rationale for going forward with this. Now, I discussed this in a podcast a couple of years ago with John Castellan, and it turned out that that assumption was overly simplistic,

although it wasn't known at the time. So since that time, Mendelian randomizations have been done,

that HDL cholesterol is causally linked to favorable cardiovascular disease outcome.

“By the way, that's the exact opposite of what the Mendelian randomizations have showed us about LDL cholesterol.”

Every Mendelian randomization that has looked at the level of LDL cholesterol, again, genetically controlled to a large extent, has found the opposite, that it is indeed causally related to bad outcomes. But we don't see that with HDL. I would like to think that if people knew that 30 years ago,

it might have saved some of the pain that was coming our way, but at the same time, maybe we wouldn't have obacetra piped today. So I don't want to be too much of a revisionist on history. The point here is the Mendelian randomizations would suggest to us that simply raising HDL cholesterol is not going to reduce cardiovascular events by itself.

Another point that wasn't known at the time that is known today, that's been reinforced by human genetics, is that individuals who have a loss of function variance in the in C-TEP have markedly elevated HDL cholesterol, and in some analyses, at least have lower cardiovascular disease risk,

but that benefit appears to track with reductions in their non-HDL cholesterol, not with the increase in HDL cholesterol. In contrast, loss of function mutations in the HDL receptor SRB1, remember I talked about how when we were dealing with direct versus indirect, reverse cholesterol transport.

The direct route is what allows the HDL to take cholesterol straight to the liver or to the gut and transported through the SRB1. So if you have a loss of function mutation in the gene that codes for SRB1, what's going to happen. You're going to have a defective transporter.

Your HDLs are not going to do a good job in getting cholesterol out of them into where they need to go.

“The HDL cholesterol is actually going to go up, isn't it?”

So those patients walk around with very high HDL cholesterol and yet they have a higher increase in coronary artery disease risk. Just as an aside, a very, very close friend of mine, who I've known for almost 20 years,

has always had very high HDL cholesterol and low LDL cholesterol.

And we used to always marvel at his lipid panels. You know, this was literally 20 years ago. And as I got deeper, deeper, deeper into the weeds of this, a few years ago, I said to him, "Hey brother, I know your HDL cholesterol is 110 or 120 milligrams per desoliter

and your LDL cholesterol is 60 or 70 milligrams per desoliter." And that almost assuredly portends a good outcome here. Do me a favor and just get a calcium score. Because I just want to be sure you don't have one of these SRB-1 mutations. And if you do, you would look exactly like you do,

but you'd be riddled with heart disease. And unfortunately, that turned out to be the case. And so he did have a very aggressive finding on his calcium scan and had a lot of calcium there. Fortunately, none of it was so far along that he's not going to be totally fine.

And he's now being treated and everything's going to be fine. But I point that out to just say, "Do not assume that because of a person as high HDL cholesterol or low LDL cholesterol that they're necessarily safe." Okay, so all of this is to say that the biology here is super, super complicated.

Okay, so let's now talk about the various C-Tep inhibitors.

So the very first of these, which you can be talked about this on the podcast

with John a few years ago, was Tercetra-Pib.

“And this is the one I talked about because I really remember this one well.”

This was a Pfizer drug. It was put into a study paired with a tourvestatin, which was about to come off patent. And everybody was excited because a tourvestatin had all of its benefits that were demonstrated over and over again in lowering LDL cholesterol and lowering cardiovascular events.

They then pair it with this drug, which doesn't just further lower LDL, but raises HDL. Everybody thinks this is going to be a home run. The drug gets stopped prematurely in 2006 because of increased mortality, which was secondary to it raising blood pressure. Now, this turned out to be an off-target toxicity,

meaning the drug was doing something that was raising blood pressure that had nothing to do with C-Tep. And it's unfortunate for that drug and that company, but none of the C-Tep inhibitors that have followed have suffered that limitation. So fast forward about six years to Dalsetra-Pib,

which is a rose drug, this raised HDL cholesterol by 30% to 40%. But it didn't really meaningfully lower LDL or APOB, and not surprisingly then, given what we know today, which is it's not the rise of HDL that matters. It's the fall of LDL or APOB that matters.

This didn't move the needle and the drug was abandoned. So it just didn't, it looked like it had favorable findings in biomarkers, but there were no good outcomes. No bad outcomes, no safety side effects, but the drug was pulled by a rose in 2012.

Fast forward a little bit more to have a Cetra-Pib.

This had a much bigger effect on HDL.

“It was increasing it by over a hundred percent,”

so more than doubling HDL cholesterol. LDL cholesterol was falling by about 30%. APOB falling by about 15%. And even LP little A, which I'm going to talk about in a minute,

the client by about 20%, but ultimately that trial

was terminated after a median follow-up of just about two years. And in retrospect, when you look at all of the data, it seems that the initial belief of the LDL reduction was probably overstated. Whereas when you looked at the relevant metric of APOB reduction,

it was about 12 milligrams per deciliter, probably not big enough to move the needle over two years. Now, a 12 milligrams per deciliter, reduction in APOB over the course of your lifetime, of course would move the needle, but not over a couple of years.

So they did another study that also failed to find a benefit and then Lilly pulled the drug on that drug in 2015. That was followed up by another study called Reveal. In this trial, Merck was looking at a drug called Anacetra-Pib, and it was adding it to a tourvestatin therapy

to reduce coronary events. This study, I believe, did see a reduction in coronary events of 9 or 10% over a median follow-up of about four years. And there's an extended follow-up of another two years that demonstrated a further reduction of events

to about 12% over about six years. And, you know, the magnitude of that benefit was consistent with what would be predicted from the degree of APOB lowering. So it was a modest effect. This was not kind of a banger effect,

and really got to remember when this is happening. This is happening as the PCSK9 inhibitors are coming online, and these things are like blowing the doors off of these metrics.

But here's what was important about this study,

is that it really was a proof of concept that CTEP inhibitors could reduce cardiovascular events. They could lower APOB particles, and they were largely risk-free, if you didn't have these off-target effects.

But, because this drug had another odd side effect, which is it had a very long half-life, and it was retained in fat cells. Now, to be clear, no one was able to demonstrate that this posed a problem,

but Merck decided to pull the plug. Now, I don't, I mean, I'm totally making this up

“and speculating, we all remember that Merck had what I consider”

one of the best drugs ever, Viox, and was probably too late to put a black box warning on that, which is what they should have done. Instead, they ultimately got called out,

had to pull this drug off the market to this day. Many patients, myself included, resent that, and wish that they had just put a black box warning on it.

And so maybe they were a little bit gunshot in this regard,

but nevertheless, that drug got yanked. So you go, what is that? So you go, what is that? So you go, what is that? So you go, what is that?

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And the US, we will wait until hard outcomes are done.

So until you see a mortality benefit or a mace reduction, major adverse cardiac event reduction, this will not be proof. So US is going to lag by a couple of years here. Let's talk about what I really want to talk about. It's not that I didn't want to talk about all this stuff.

I really did. But I want to now get into the part that is super exciting to me, which is brain biology and apoe. So the brain is one of the most lipid rich organs in the body.

“And of course cholesterol is one of the most important structural components of neuronal”

membranes, synapses and myelons. So without cholesterol, the brain is not going to function. But there's a catch, right? The brain lives behind a paywall. We call it the blood brain barrier.

It's not really a paywall, but I just want to say that. So the brain lives behind a blood brain barrier. And that blood brain barrier separates the brain's cholesterol economy from the rest of the body. So the lipoprotein particles that we measure in the blood are essentially sequestered from the brain.

And as such, the brain cannot rely on circulating cholesterol the way the liver can. Instead, the brain runs its own semi-independent lipid management system, which transports its own lipoproteins. Now in the periphery and the rest of the body, outside of the blood brain barrier, cholesterol balance depends on a very coordinated system of lipoprotein particles.

We've talked about this.

“We talked about the HDL particles, which are built around AOA1.”

They accept cholesterol from cells, transport back to the liver, sometimes give them to LDLs, to take them back to the liver. All of this stuff is going on. And I didn't even get into the rest of that stuff. But we know that as the liver excretes bile, bile travels through the gut, the gut has another

check in there where it gets to bring cholesterol in, determine if we need it or not. If not, we excret it, if yes, we bring it back in, there's like the body is really, really pretty marvelous when it comes to this. But the brain uses a very different set of proteins to mediate this. Now instead of using AOA1, which is the protein on the HDL that is largely responsible

for this accounting, it's lipoproteins, the one in the brain are organized around something called apo lipoprotein e or apoe. So astrocytes and microglia synthesize apo e containing particles that shuttle cholesterol and phospholipids to neurons.

These particles support membrane repair and synaptic remodeling, and basically the overall

lipid homostasis within the CNS. Now the efficiency of that system, of course, turns out to be highly genotype dependent. So most people carry two copies of an isophoram for the gene that makes this protein called apoe3. So there are three isophorams, apoe2, apoe3, and apoe4.

This is a bit of the problem with the nomenclature here. Whenever I'm talking about the gene, I'm talking about the all-caps version. So capital A, capital P, capital O, capital E, and then the number 2, 3 or 4. You get two of those, two genes, one from mom, one from dad. So if there are six possible combinations, two, two, two, three, two, four, three, three,

four, four, four. Each of those will yield a slightly different protein. The protein is called apoe, no number, just apoe, and it's no caps. So it's just a little A, P, O, E, no caps.

“So that's how you know if you're thinking about the protein or thinking about the gene”

that codes for the protein. So if you look at the apoe protein that is made by two copies of the apoe 3 gene, we call this the wild type, it handles cholesterol transport in the brain really well. But if you look at the protein, the apoe protein that is made by one or two copies of the apoe 4 gene, it does not.

So if you look at the protein made from one or two copies of an apoe 4 gene, it's less efficiently lipidated, it interacts differently with transporters, and it forms lipoprotein particles that are less structurally stable and less effective at moving cholesterol.

And what's really amazing, by the way, is an aside, is all of this comes down to a single

amino acid substitution. And for anybody who cares, it's a cysteine to an arginine substitution at position 1, 12. And that one little change, alters the proteins shape, and all of its downstream behaviors. And of course, this isn't unique here. And if you look at something like sickle cell disease, it's the same sort of thing.

It's one amino acid substitution that completely changes the way a red blood cell functions. In this case, you know, through hemoglobin.

Well, we care because if cholesterol isn't properly transported, it's going to build up. And lipid droplets that form inside of astrocytes and microglia, they cause problems, right? The membrane composition shifts oxidative stress, because remember cholesterol is high

“ly sensitive to oxidative stress, that's what's leading to atherosclerosis.”

It increases, amoloid clearance becomes less efficient, and inflammatory signals rise. And if that sounds like a bad thing, then you understand enough about Alzheimer's disease already, which is amoloid accumulates inflammation increases, and over a long enough period of time, often decades, this impaired ability to traffic lipids is what contributes to

synaptic dysfunction and ultimately to neuronal death.

So this is why APO E4 is a concern. If an individual has one or two copies of this gene, they are at an increased risk for Alzheimer's disease. Now, we also know that this is not a deterministic gene. There are lots of people that are walking around with APO E4 genes that are doing just fine

in advanced age.

“So I don't want to be sitting here sending fear signals to those individuals.”

But we have to acknowledge that on average, statistically speaking, if you have one or two copies of that gene, you are basically getting sped up in your brain aging. And what that effectively means is if you have two copies of an APO E4 gene, your probability of developing clinically significant cognitive decline is going to be about two decades sooner than a person who's got two copies of an APO E3 gene.

There are lots of things that can modify this. We've talked about some of them. We've talked about Clotho, KLVS. We've talked about all the lifestyle factors that can make a difference. But I just want to acknowledge the obvious here.

Now, I think kind of at first glance, I think C-TEP inhibition might not really matter

to this discussion because it operates in plasma, where it facilitates the exchange as we talked about between cholesterol, Ester, between the different particles of lipoproteins. The cholesterol Ester is that move between HDL and LDL. And this creates a larger HDL particle where APO A1 stays on longer and it's cleared more slowly.

So again, APO A1 concentrations increase.

“That's why we see HDL cholesterol go up.”

So what does this have to do with the brain? Well, APO A1 is a relatively small protein and therefore small lipid pur HDL particles, which contain APO A1, can indeed cross the blood-brain barrier in limited amounts. So by increasing the circulating pool of APO A1, the C-TEP inhibitors can increase the availability of functional APO A1 within the CNS.

So in the context of APO E4 patients where endogenous lipid transport is less efficient, a greater concentration of APO A1 could augment cholesterol e-flux, and at least partially offset the impaired functioning APO E protein, the APO E mediated trafficking of that protein. Now, in addition to that, of course, Obacetra PIB confers all the usual three-brovascular benefits through the well-established, atherotic, atherosclerotic actions by lowering

APO B, et cetera. In addition, functional HDL particles can carry lipophilic anti-oxidants as well and move them.

So basically, increasing HDL concentration, especially HDLs that are small, but yet functional

it can still get into the CNS, may raise the antioxidant content within the circulating HDLs and to a limited extent within the CSF. So enhanced antioxidant availability could help attenuate the oxidative stress and lipid proxidation process, which, of course, is also known to amplify neuroinflammatory signals. Now, again, this framework is somewhat speculative, but it is biologically coherent.

It also offers a plausible explanation for why the most pronounced biomarker effects in the broadway sub-study, which I'm going to discuss here in a second, are observed in the APO E for E4 individuals. Because this is a group in whom lipid trafficking is the dysfunctional lipid trafficking, I should say, is the most noted.

And therefore, this group in theory should benefit the most from everything I just said. Okay, so let me just go back to this study, because I'm kind of getting ahead of myself in the spirit of trying to explain the biology. So let's go back to the broadway study. So remember, this is the one where there was a pre-selected endpoint.

disease. And the primary endpoint was a change in plasma phosphorylated tau 217 known as p-tow 217 over the period of 12 months from baseline to a year out. They also looked at some secondary endpoints, which were changes in the ratio of p-tow 217 to amily beta 42 to 40 ratio, and then p-tow 181.

And I think called glial fibrillary acidic protein or G-F-A-P and neurofilament light chain or NFL.

I just want to point out that p-tow 217 is probably the most important of these, at least

we believe that today, because it is the most highly correlated with the findings that we see on a type of pet scan that is used to measure tau. And that pet scan and its results tend to be the most highly correlated with the clinical outcomes that we see.

“So that's why they chose p-tow 217 is the primary endpoint.”

The participants were stratified by their apoegene types, specifically they looked at 3-3s, 3-4s and 4-4s, and then all the related subgroups. Okay. So in the final biomarker analysis, the rover 1500 participants, median age of 67, 2/3 of them are male.

Now, these are patients without dementia or cognitive impairment, but they did have cardiovascular disease.

It's always important to just remember what your patient population was.

Let me spend one more second just going over the biomarkers. So as I said, plasma p-tow probably the strongest predictor we have in the periphery that correlates with Alzheimer's pathology. Again, I mentioned why.

“The amyloid pet positivity and tau aggregation are probably the best thing we can do to predate”

clinical stage symptoms. AB 4240 ratio reflects amyloid biology, so as AB 42 becomes sequestered into plaque with the brain circulating AB 42 declines relative to 40, which lowers that ratio.

If you look at p-tow 217 to that ratio, it just integrates these two.

G-fap is a marker of astroglial activation and NFL is a marker of axonal injury and neurodegeneration. It's not specific to Alzheimer's disease, by the way, but when levels are rising, it indicates an neuronal damage. So if we take these things together and look at their results, what did we see? So across all participants, Obesetra Pib significantly attenuated the increase in p-tow

217, the primary outcome compared to placebo over 12 months. So if you take everybody, the adjusted mean percentage increase in the placebo group was 5%. So p-tow 217 went up by 5% across everyone in the study over a year and in the placebo group and then the Obesetra Pib group only went up 2%.

Now what's interesting is if you start to look at the subgroups, so in the subgroups, if you look at the just those that had an e4, so this was people who were e3e4 or e4e4, the difference is a little more stark. In the placebo group, you saw an increase of p-tow 217 by over 7% whereas in the Obesetra Pib group, it only went up 1.5%.

“Now what if you just looked at e3e4 and e4e4 in people over the age of 70?”

So again, what we're doing is we're taking that same population but now we're looking at the people who are at even higher risk just based on age. And here we saw that in the placebo group, p-tow 217 over the course of a year rose by almost 15% but it went up only by 6% in the Obesetra Pib group. Again, that was statistically significant.

But the most interesting finding for me, and I think anybody who would look at the paper, is what happened in the admittedly small subset 29 people of e4e4s of any age. In this population, the placebo group saw an increase of almost 13% 12.7% of p-tow 217 over the course of a year and yet in the group on Obesetra Pib, they actually saw a reduction in p-tow 217 by nearly 8% creating a difference of over 20% between those treatment groups

and that was again highly statistically significant, despite the small number. So all of this is to say that something really interesting could be happening in these

So this is a 1,500-person trial, 29 of those people were e4e4 as a general rule in the population.

“e4e4 is about 2% of the population, but e3e4 is about 20% to 25% of the population.”

So there's still a lot of people out there who would benefit from this. We're just seeing an enormous impact in these people. The overall population, again, the effect size is statistically significant. We don't know if it's clinically significant. I won't go into all the other biomarkers just for the sake of time, but we're going to

link to the study in the show notes so you can look and see all of the other biomarkers. But everything moved in the right direction. There was not a single biomarker for which Obesetra Pib didn't do exactly what you would want it to do. This was true in Pitout 217. This was true in NFL GFAP.

Of course, the impact was most notable and most significant in the e4e4. So there's one figure that you can look at where you see the effect on the e4e4s and it's profound. So I'll go over that figure because I already gave you the Pitout 217 where you see a 20% difference between placebo and treatment in the NFL.

It's a 17% difference in the GFAP. It's a 15% difference in the Pitout 181. It's almost a 14% difference in the AB 42 to 40 ratio. It's about an 8% difference and in the ratio of the ratio, the Pitout to the AB 4240. It's almost a 23% difference.

So how do we interpret this? Well, let's be cautious here.

So first and foremost, this is a biomarker study.

It's not a cognitive outcomes trial. There are no formal cognitive tests that were included here. And we don't know for certain if these biomarker changes would translate into preserved cognition or slower decline or reduced incidence of dementia. As I said, Pitout 217 is a very well-validated biomarker.

So everything looks very optimistic but without the outcome trial, we don't know. Second thing we don't know is this is a short study. There's only 12 months, Alzheimer's is a disease that unfolds over decades.

“Do we know if we looked at over a long enough period of time with this benefit be maintained?”

I already talked about the size of the subclass, very small group. Sometimes you can see extraordinarily results in small groups and it's a bit of a weird statistical outlier and we don't know what it's going to look like in a larger cohort. I think the last point I would make here is less of a knock but it's just that we don't know exactly why this is happening.

Now to be clear, we don't know why Clotha works either and yet we still think it's very exciting and interesting. We don't know how Clotha works. I mean, we don't even understand how Clotha impacts its targets in the brain since it doesn't appear to Clotha cross the blood-brain barrier.

So all of that is to say we know a bunch of things that Obacetra Pib does. We know that it modifies HDL particles and lowers LDL and APOB, reduces LP little A. But it's hard to say which of these are the ones that are contributing and I personally find the HDL APOA1 story to be the most compelling argument here. So what can we conclude?

“So I think we can say, look, this is a biomarker study that was internally coherent and”

very genotype specific and I think it has very high biological plausibility. I think we have to be cautious because biomarkers don't necessarily establish clinical benefit. We need more data but I'm very excited and I think personally that this signal is strong enough to justify a dedicated prospective prevention trial that should include cognitive outcomes, imaging, longer follow-ups, and frankly larger genomic stratified groups.

Now such a study would need to be enriched for APOE4 carriers. So we'd want lots of E3 and E4. So if I were designing that study, I'd want as many, I'd want every E4 for on the planet

that I could get enrolled in that study and I'd want basically two thirds of the patients

to be at least a three-four. In my mind, you want people who are completely cognitively intact in mid-life or slightly older. So these are probably people in their 60s, maybe 70s, but again, completely cognitively intact, no evidence of MCI, and you're going to need to track these people for quite a long

period of time. So it's going to need to have longitudinal cognitive endpoints that are going to be sensitive to early decline. It's going to have to have serial plasma biomarkers, maybe some imaging studies including amillowator tau pet, and it needs to run for several years.

So look, I'm not suggesting that this is an easy thing to do. I'm just suggesting that if we lived in a parallel universe where resources were unlimited, that's the study that you would do to figure this out. So look, it's hard for me to mask my personal optimism around this. I love the biological plausibility of this, and I think that Obacetra Pib has done something

the impact that I think it's going to have from a cardiovascular disease standpoint, which

is to say it's going to have a significant impact on LDLC and APOB.

“I believe it will likely show a reduction in events, certainly over a long enough period”

of time. The impact on LP Little A is very interesting to me, and the fact that it is metabolically neutral or potentially positive is also very exciting, and then you layer this on as well. This is a drug I'm very excited about, and look forward to learning more about the approval process in the United States.

“Again, I don't know exactly where it is in that life cycle, but I know it'll probably”

still be a couple of years after the European approval, which will lead to the launch of

this drug in the second half or last quarter of 2026.

So, that'll wrap up our story on Obacetra Pib. Hope you guys found that is interesting as I did. Thank you for listening to this week's episode of The Drive.

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